Genome-wide association studies (GWAS) in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually-dimorphic complex autoimmune disease.We performed a chrX-wide association study (XWAS), including genotype data from five GWAS (from Italy, UK, Canada, China, Japan; 5,244 cases, 11,875 controls).Single-marker association analyses found ∼100 loci displaying P<5*10-4, with the most significant being a signal within the OTUD5 gene (rs3027490, P=4.80*10-6; OR=1.39 CI=1.028-1.88; Japanese cohort). While the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR=1.17, 95%CI=1.09-1.26; P=9.93*10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asians pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P=6.2*10-9, OR=1.33, CI=1.21-1.46). Indeed, rs7059064 tags a unique LD block including seven genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a super-enhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is predicted to target also FOXP3, the main T regulatory cell lineage-specification factor. Consistently, OTUD5 and FOXP3 RNA levels were upregulated in PBC cases (1.75- and 1.64-fold, respectively).This work represents the first comprehensive study of the chrX contribution to the genetics of an autoimmune liver disease and revealed a novel PBC-related genome-wide significant locus.
Rosanna Asselta, Elvezia Maria Paraboschi, Alessio Gerussi, Heather J Cordell, George F Mells, Richard N Sandford, David E Jones, Minoru Nakamura, Kazuko Ueno, Yuki Hitomi, Minae Kawashima, Nao Nishida, Katsushi Tokunaga, Masao Nagasaki, Atsushi Tanaka, Ruqi Tang, Zhiqiang Li, Yongyong Shi, Xiangdong Liu, Ma Xiong, Gideon Hirschfield, Katherine A Siminovitch, Canadian-US PBC Consortium, Italian PBC Genetics Study Group, UK-PBC Consortium, Japan PBC-GWAS Consortium, Marco Carbone, Giulia Cardamone, Stefano Duga, M Eric Gershwin, Michael F Seldin, Pietro Invernizzi